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 October 24, 2016
What caused the Black Death and could it strike again?

 In what annals has it ever been read that houses were left vacant, cities deserted, the country neglected, the fields too small for the dead and a fearful and universal solitude over the whole earth?... Oh happy people of the future, who have not known these miseries and perchance will class our testimony with the fables.


The medieval Italian poet Petrarch, describing the onslaught of the Black Death in 1348, was prescient. Today, we can't imagine its lived reality. To sense what the Black Death was really like, you have to imagine that a third of the people you know, or of the human beings you can see walking down the street, suddenly vanish. The known world with a third fewer of its people within a span of six years is unthinkable. And it happened only once in history.

During the onslaught, there'd be no place to bury all the bodies; people would lie abandoned in the street, or curled up on the sidewalk, choking for air until they died. You'd meet a friend for lunch; by nightfall he'd be dead, dining with his ancestors in Paradise, as the Italian poet Boccaccio put it. You would never know whom the arrow would strike next -- your wife, your children, your friends, your parents, or you yourself. A large, exquisitely painful swelling might erupt under your arm or in your groin, or -- worse -- you might feel well one minute and the next start spitting blood. And that blood-spitting was always fatal.

There had been terrible epidemics before: the Athenian Plague of 430 BCE, which decimated Periclean Athens (and was probably caused by typhus); the Antonine Plague of 165-180 CE, which made dramatic inroads on the Roman Empire of Marcus Aurelius, and which was likely smallpox; and, worst, the Justinian Plague, 541 CE, which killed millions, spreading around the Mediterranean and up into France, Germany and perhaps the British Isles.

Like the Black Death, the Justinian Plague -- named after the Byzantine Emperor Justinian who nearly died of the disease -- was caused by the plague germ Yersinia pestis. But the dynamics of the Black Death and the Justinian Plague were different. The Justinian plague struck randomly, not systematically like the Black Death; most records suggest it wasn't generally contagious; it surely did not wipe out a third of the known world, though the true death toll is impossible to ascertain.

The Justinian Plague is known today as the First Pandemic; the Black Death (the Second Pandemic) followed some 800 years later, between 1346 and 1353. The Third Pandemic began in China at the end of the 19th century and spread to Africa and both North and South America, where it still occasionally causes human infection. Over a 30-year period, the Third Pandemic killed some 12 million people in India alone, but -- except for several short-lived, violent outbreaks of pneumonic plague in Central Asia -- it was positively sluggish compared with its predecessors.

All plague is deadly. Untreated, the bubonic form -- transmitted by fleas through the skin, and notable for enormous swellings of the lymph glands called buboes -- kills about 60 per cent of those infected. That's the mild version. Pneumonic, or lungborne plague, transmitted through the air from one person to the next, kills close to 100 per cent.

To understand the difference between the various pandemics, it's important to grasp that virulence (deadliness) and transmissibility (the ability to spread from one host to another) are not the same thing. The Black Death wasn't deadlier than other plagues: it was more transmissible. It blazed from town to town, from country to country. It wiped out entire households; some buried all their children before dying themselves. Physicians feared to treat it: most attendants became ill, and many died. Nuns took in the dying and nursed them, then went their own way to death, or heaven. Men took to horseback and fled, till the disease struck them down a few short days later. And thus the plague spread, like wildfire.

Though pandemics happen by accident, they do not happen without cause. You start with one of the most virulent of all disease germs in wildly transmissible form, able to move equally well through the air or via ministrations of the human flea. Then you mix in the peculiar social circumstances of the Mongol Empire, unique for the masses of Mongol riders moving swiftly across Central Asia and beyond. The Black Death grew out of a precise alignment of circumstances. There were four stars in that night sky: germ, host, Empire, and flea. Without those four dark stars shining in their particular conjunction, the Black Death could never have occurred. The historic Black Death was a nightmare from our past; likely a once-in-a-world event. But once we chart the alignment of its stars, we'll be more equipped to fight deadly new plague pandemics, wherever they might erupt.

Because the Black Death was unique, many scholars have questioned whether it was caused by plague at all. The zoologist Graham Twigg, in his book The Black Death: A Biological Reappraisal (1984), argued that plague as we know it simply can't spread as fast as the Black Death. In that, he was right. Unfortunately for Twigg's credibility, he proposed lung-borne anthrax as the agent of the Black Death, overlooking the fact that anthrax isn't a lung-borne disease.

Two researchers at the University of Liverpool, the late Christopher Duncan and Susan Scott, proposed an Ebola-like virus as the culprit. Yet neither the pattern of transmission nor the symptoms described remotely resemble Ebola, or any hemorrhagic fever. Neither anthrax nor Ebola are shed from the lungs: they can get into the lungs and make you sick, but they can't get out again.

There were other skeptics, too, such as the historian Samuel K Cohn at the University of Glasgow, who analysed the spread of the Black Death from town to town, country to country, and honed in on one incontrovertible point: the Black Death spread faster than plague does today.

Kenneth Gage, a plague ecologist at the Centers for Disease Control and Prevention (CDC) in Fort Collins, Colorado, told me back in 2003, while I was working on my book Plague: The Mysterious Past and Terrifying Future of the World's Most Dangerous Disease, that the time was coming when no one would believe that the Black Death was caused by plague.

But in 2004 a team of French researchers analysed ancient DNA taken from the tooth pulp of skeletons from Black Death cemeteries, and found persuasive genetic evidence of Yersinia pestis. In 2011, an international team lead by Hendrik Poinar of McMaster University in Hamilton, Ontario used ancient DNA to develop a genetic blueprint of the Black Death pathogen. There could be no mistake: the Black Death was plague.

That is the first dark star: Yersinia pestis. Plague is the deadliest bacterial disease known to humankind.

Poinar's blueprint did not reveal special genes for added virulence, and did not solve the Black Death's essential mystery: what made it much worse than all other plague outbreaks, and the deadliest pandemic of all? At a loss, Poinar proposed that the distinctive ferocity of the Black Death could be found in the poverty and filth of the medieval world, not the germ.

But he was likely wrong. To grasp the Black Death's power, we have to look elsewhere -- to the marmot, its original host and the second dark star. We know that the Black Death started in Central Asia, almost certainly among marmots -- large, intensely social rodents often hunted by humans. Marmots are so ubiquitous and characteristic that Marco Polo referred to them as 'Pharaoh's rats'. They were the source of the 20th century's three great pneumonic plague outbreaks: two well-known Manchurian plagues of 1910 and 1920 (which killed 60,000 and 10,000 respectively), and a third little-known outbreak in 1917-18 in Shansi, China (which killed some 16,000).

Poinar's analysis, in fact, suggested the importance of the marmot in the Black Death. Modern marmot plague strains have genes that allow them to 'ferment glycerol' -- that is, to make use of a building block of fat found in hibernating animals. Marmots hibernate, and plague germs can maintain themselves in the somnolent animals without killing their hosts. In the spring, as the marmots awake, the infection wakes up too, sickening the marmot and contaminating its fleas with bacteria-laden blood. Many modern strains, particularly those derived from rats, which do not hibernate, cannot ferment glycerol. Interestingly, Poinar's reconstructed genome shows that the ancient Black Death strains could ferment glycerol too, further evidence of a marmot origin to the Black Death.

The physician Wu Lien-teh noted in the early 20th century that marmot-plague infections later spread by fleas have an unusual ability to reach the lungs of human patients and provoke a pneumonic outbreak. In the 1920 epidemic, Wu treated the index case, a woman who had contracted bubonic plague through the skin, from a marmot, and later developed a secondary pneumonia. Despite his best efforts, the pneumonic strain escaped the hospital, fled with soldiers on a railway, and caused 10,000 deaths before physicians and public health workers got it under control.

The late Russian plague expert, Igor V Domaradskij, who was also the co-designer of the Soviet bioweapons programme known as Biopreparat, told me in 2003 that the only plague strain the Soviets worked with was marmot plague, whose explosive power they well understood.

Vladimir Motin, a Russian plague expert now working at the University of Texas Medical Branch in Galveston, agrees that the marmot-derived strains from Central Asia are more powerful and dangerous than plague strains found elsewhere in the world. But he adds that no one yet knows why. You can't read transmissibility by looking at a genetic blueprint, though the explosive behaviour of marmot-derived plague is clear from recent history.

The second dark star, the host -- the Central Asian marmot -- is therefore likely fixed in the firmament as carrier of the most explosive form of the disease.

The third dark star is Empire. Surviving accounts from medieval times place the origin of the Black Death in 'the East' or 'the Land of Darkness' -- a reference to Central Asia, or perhaps to China. The earliest plague graves ever discovered, by the 19th-century Russian archaeologist Daniel Abramovich Chwolson in what is now Kyrgyzstan, dated to about 1339 -- shortly before the Black Death exploded across Asia and Europe. Those graves lie in a Nestorian Christian cemetery near Lake Issyk-Kul, not far from what is now Xinjiang, or western China. There's no reason to think that these quiet Christians in their remote habitation were the index cases of the Black Death, but they were surely among the early ones.

The Black Death found its way through small villages and Mongol nomad settlements alike, sweeping down through cities and farm regions, through army encampments and caravans, making use of the rapid Mongol transit system of horse relays, which sped soldiers on a medieval pony express through the empire. They dashed throughout the four kingdoms ruled by the grandsons of Chinggis Khan, and plague rode with them, throughout Uzbekistan and Kazakhstan, into Persia and the Crimea. From there, it spread to Genoese traders encamped around the trading city of Caffa on the Black Sea, and thence to Constantinople on the Dardanelles, into the Mediterranean, to the islands of Crete, Sardinia and Sicily, before making its way to Genoa and exploding on the European mainland.

How can it be said that all these social and ecological conditions and locales were alike, and equally vulnerable to plague? Of all the explanations for the Black Death, given its spread and its indiscrimination, the 'social and ecological' conditions seems to me to be the weakest. You can't compare a London slum to a Persian palace, or to a Nestorian village. They are, quite literally, worlds apart.

But how did the Black Death move into and among the Mongol population? Did the Mongol army carry marmots with them as they rode across Asia? Did Mongol traders stuff grain and attendant rodents into their saddle-bags, as the historian William McNeill, writing in his book Plagues and Peoples (1976), suggests? McNeill was thinking of rats, but Central Asian marmots can be one or two feet tall, so inadvertent Mongol transport seems unlikely.

The origins of the Black Death are probably much simpler: it came from marmots and infected hunters, as it has again and again. What made the Black Death different is the way it spread.

Though plague is a disease of rodents and a dead end in human beings, the Black Death didn't spread in marmots. It spread in people. Plague moved fast because Mongols on horseback, the third dark star in the constellation of plague, moved fast. The rapid, mysterious transmission of the Black Death can mean only one thing -- it had become, at least for a time, a swiftly moving, efficiently transmitting human disease carried by horseback; an effective human pathogen spread by the swift riders of the realm.

Bit by bit, a picture of the Black Death is emerging. DNA reconstruction by Chinese researchers shows what is called a 'polytomy', a flowering of new strains shortly after the outbreak began. Some of those strains appear to be genetic dead ends, but others gave rise to all later plague strains in the world today.

This suggests, not a process of genetic drift, but an evolutionary adaptation: plague strains were adapting to a new -- human -- host. That this adaptation was an evolutionary process produced by the action of natural selection, rather than just a series of incidental and meaningless mutations, seems evident to anyone familiar with the way infectious disease agents always adapt to new hosts. For instance, rodent pox likely adapted to human beings to become smallpox; likewise, poliovirus learned the subtle tricks of human immunity, and Mycobacterium leprae evolved to produce the human disease we know as leprosy.

Robert Brubaker, a microbiologist and plague expert from Michigan State University, has been poking, prodding, squeezing and beating the plague germ for more than 50 years to force it to reveal its secrets. He argues that germs don't generally evolve to kill their hosts, because a dead host is less likely to spread infection to a new host.

The evolutionary epidemiologist Paul W Ewald of the University of Louisville subtly refines the point: in vector-borne diseases -- those spread by insects -- an infection can move from a dying host as readily as from a mobile and vigorous one. A mosquito or a flea can bite you whether you're marching about outside swinging a machete, or chasing a child, or lying supine on your mattress. Here, the level of virulence becomes important: any animal that has a higher degree of bacteremia (more bugs in the blood, a result of severe illness) is more likely to transmit those strains to a flea, and thence to the next host.

This means that natural selection will put extreme pressure on plague strains transmitted by fleas to be very dangerous. High levels of bacteria in the blood produces sepsis, or blood poisoning. Sepsis is always likely to be fatal -- for plague, death rates approach 100 per cent.

Yet fleas won't bite a dead host. So in order to achieve that level of bugs in the blood, and yet prevent the host from being killed off too quickly, the plague germ silences immunity by inhibiting production of inflammatory molecules, called cytokines. This is why a Mongol could ride for days after being infected. He had no fever, no swollen glands, no symptoms of illness at all -- until he fell over, his organs almost replaced by plague bacteria, his blood almost a pure Yersinia pestis culture.

'Plague is a stealth infection,' Brubaker likes to say.

But one more dark star had to come into alignment for the Black Death to take hold: the flea. Because buboes have been observed in rat-flea bites, experts have argued since the early twentieth century that the rat flea (and thus, rats) were at the root. But that is not the case.

According to the CDC plague expert Kenneth Gage, the fourth dark star in the Black Death firmament was Pulex irritans, the so-called human flea. Pulex lives, not so much on human skin or in human hair, but in clothes and bedding; in the 17th century, the London diarist Samuel Pepys described clouds of fleas tormenting travellers forced to sleep in unwashed sheets. Discarded linen and clothing, even from a dead plague victim, might well be reused, since no one understood how the plague spread.

With those four dark stars aligned, what we can surmise is this: the Black Death was caused by the plague germ Yersinia pestis, which evolved in Central Asia. It spread to human beings from marmots, the original and deadliest source.

Once ensconced in human beings, the germs rapidly evolved, leading to new strains that were more effective as human pathogens, though no one knows exactly what DNA mutations drove the change. We know from the historical records that the Black Death spread lung-to-lung, as did marmot-derived strains during 20th-century plagues in Manchuria. Medieval texts describe both blood-spitting -- pneumonic transmission -- and buboes, indicating flea-borne transmission, almost certainly through the ministrations of Pulex irritans.

The Black Death burned out around 1353, but it gave rise to plague strains that continued to circulate around Europe until the mid-18th century. The last major Western European epidemic broke out in 1720, in Marseilles. Epidemics erupted in Russia and the Levant through the late 19th century. In these later outbreaks, though, 'blood-spitting' diminished and then disappeared from the records as a primary symptom. The pneumonic plague of the Black Death, with its extraordinary death rates, was just too virulent a disease to linger and become a permanent human respiratory affliction. After the Black Death, the principal mode of spread from person to person was almost certainly the human flea.

Whether plague strains during the Renaissance were descended directly from the Black Death or augmented by fresh imports from Asia along the slow, ponderous caravan routes we know as the Silk Roads, we still don't know.

We also don't know exactly how plague moved into southern China, the source of an entirely new outbreak of this ancient disease. During the Black Death, or through natural rodent spread, the plague germ moved through that vast country and eventually took up residence in Yunnan. There, it lost its ability to ferment glycerol. Somehow, crouching in the rats and burrowing into the fleas of that crowded district, the plague germ, freshly decked out in its new form as Yersinia pestis orientalis, jumped aboard ships and sailed across the world, to spread death and misery to Africa, India, South America, and the western United States. That was the Third Pandemic, launched in the late 19th century: its effects are with us still.

And deadly, explosive marmot plague is with us too. In 2015, Thomas Zimmerman, a researcher who has worked at the US National Security Council and the Department of Defense, described China's ambitious new proposal, called OBOR ('One Belt, One Road'), to build a massive highway from southern China across the mainland into southern Russia and Belarus through to Poland, Germany and down into France. Tentacles also reach into Uzbekistan and Pakistan. The point of OBOR is to revive the old Silk Road, selling industrial goods -- trains and planes -- instead of silk, spices and porcelain.

Vladimir Motin views this looming superhighway, which runs through the worst plague habitat on Earth, with a touch of dread. The explosiveness of marmot plague has never diminished. And marmot plague outbreaks still happen in China, Kazakhstan and elsewhere with irregular but dismal frequency. Whole neighborhoods are sometimes quarantined to this day. In the age of antibiotics, in an age of hygiene where human fleas no longer torment us, we are unlikely to see a new Black Death, but two of the ancient dark stars -- marmot plague and a rapidly expanding economic empire -- could still produce pockets of explosive, deadly disease. Even with the best treatment, some 14 per cent of pneumonic plague victims still die. Marmot plague gliding silently and rapidly on high-speed trains or down a superhighway would not cause a new Black Death, but it isn't a pleasant prospect.

If we know the factors that led to the Black Death, if we thoroughly understand them, then it makes little sense to allow two of those deadly stars to align again.